Whole-exome sequencing for the identification of rare variants in primary immunodeficiency genes in children with sepsis - a prospective population-based cohort study - Publication

Publication

Whole-exome sequencing for the identification of rare variants in primary immunodeficiency genes in children with sepsis - a prospective population-based cohort study

Journal Paper/Review - Mar 18, 2020

Borghesi Alessandro, Kuehni Claudia E, Thorball Christian W, Chaturvedi Nimisha, Martinon-Torres Federico, Kuijpers Taco W, Coin Lachlan, Wright Victoria, Herberg Jethro, Levin Michael, Aebi Christoph, Christoph Berger, Fellay Jacques, Schlapbach Luregn J, Riedel Thomas, Relly Christa, Trück Johannes, Asgari Samira, Sancho-Shimizu Vanessa, Agyeman Philipp K A, Bellos Evangelos, Giannoni Eric, Stocker Martin, Posfay-Barbe Klara M, Heininger Ulrich, Bernhard-Stirnemann Sara, Niederer-Loher Anita, Kahlert Christian, Natalucci Giancardlo, EUCLIDS consortium and the Swiss Paediatric Sepsis Study

Citation

Borghesi A, Kuehni C, Thorball C, Chaturvedi N, Martinon-Torres F, Kuijpers T, Coin L, Wright V, Herberg J, Levin M, Aebi C, Christoph B, Fellay J, Schlapbach L, Riedel T, Relly C, Trück J, Asgari S, Sancho-Shimizu V, Agyeman P, Bellos E, Giannoni E, Stocker M, Posfay-Barbe K, Heininger U, Bernhard-Stirnemann S, Niederer-Loher A, Kahlert C, Natalucci G, EUCLIDS consortium and the Swiss Paediatric Sepsis Study. Whole-exome sequencing for the identification of rare variants in primary immunodeficiency genes in children with sepsis - a prospective population-based cohort study. Clin Infect Dis 2020

Type

Journal Paper/Review (English)

Journal

Clin Infect Dis 2020

Publication Date

Mar 18, 2020

Issn Electronic

1537-6591

Brief description/objective

BACKGROUND
The role of primary immunodeficiencies (PID) in susceptibility to sepsis remains unknown. It is unclear whether children with sepsis benefit from genetic investigations. We hypothesized that sepsis may represent the first manifestation of underlying PID. We applied whole-exome sequencing (WES) to a national cohort of children with sepsis to identify rare, predicted pathogenic variants in PID genes.

METHODS
Multicenter population-based prospective study including previously healthy children ≥28 days and <17 years admitted with blood culture-proven sepsis. Using a stringent variant filtering procedure, analysis of WES data was restricted to rare, predicted pathogenic variants in 240 PID genes for which increased susceptibility to bacterial infection has been reported.

RESULTS
176 children presenting with 185 sepsis episodes underwent WES (median age 52 months, IQR 15.4-126.4). 41 unique predicted pathogenic PID variants (1 homozygous, 5 hemizygous, and 35 heterozygous) were found in 35/176 (20%) patients, including 3/176 (2%) patients carrying variants which were previously reported to lead to PID. The variants occurred in PID genes across all 8 PID categories as defined by the International Union of Immunological Societies. We did not observe a significant correlation between clinical or laboratory characteristics of patients and the presence or absence of PID variants.

CONCLUSIONS
Applying WES to a population-based cohort of previously healthy children with bacterial sepsis detected Variants of Uncertain Significance in PID genes in one out of five children. Future studies need to investigate the functional relevance of these variants to determine whether variants in PID genes contribute to pediatric sepsis susceptibility.